From the pioneering discovery of antibiotics in the end of first half of the 20th century, new antibiotics, semi-synthetic antibiotics and new chemotherapeutics with antimicrobial activity, have been developed on a large scale against most intracellular and extracellular bacteria. These developments have changed the history of medicine, allowing it to reach a wide spectrum of healing, for the vast majority of bacterial infectious diseases, which racked humanity.
The Discovery of Antibiotics and Other Drugs
Thus, the discovery of antibiotics was a major milestone, a watershed, because infection could be addressed and healed, in a specific way, with a clear relationship of cause and effect, and measurable when established. This discovery greatly expanded the ability of healing in medicine, with enormous positive impact on human health and lifespans. The discovery of antibiotics in the evolution and treatment of disease profoundly influenced the research and thinking of researchers from the success achieved by this experimental model (Reeves G, Todd I. Lecture notes on immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto V A, Nicodemo A C, Lopes H V. Antibióticos na pratica medic& 6th ed: Sarvier, 2007; Murray P R, Rosenthal K S, Pfaller M A. Microbiologia Medica. 5th ed: Mosby, 2006; Trabulsi L R, Alterthum F. Microbiologia. 5th ed: Atheneu Editora, 2008).
Antibiotics were succeeded by the development and use of antifungal, antiparasitic and antiviral drugs. The “anti” drug model became a gold standard experimental model due to huge success against anti-etiologic agents, and was extended to diseases with unknown etiology against their physio pathologic process and to very similar autologous neoplastic cells, with less specificity, less selectivity and less effectivity as:                Anti-allergic;        Anti-inflammatory;        Anti-immune (Immunosuppressive);        Anti-neoplastic (cytotoxic); and        Anti-hormone.        
Thus, the new “anti” drugs brought an enormous capacity for medical intervention, with numerous benefits, with definitive and partial cures, with the prolongation of life in incurable diseases, but also with huge morbidity due to side effects related to their lack of specificity to the pathophysiology of the diseases.
The Innate Immunity
The innate immunity, in addition to preventing the entry of microorganisms and preventing their establishment, has another recently discovered vital function: discrimination between “self” and “not self” by the pattern recognition capability linked to the alarm and the command to start or inhibit an integrated immune response against an invading microorganism or to arrest, repair or inhibit a condition of destruction or self-aggression to the body, for example, in trauma, autoimmune diseases and allergic diseases, among others.
This dual capability was previously erroneously attributed exclusively to adaptive immunity. The innate immunity, through its own germinal receptors, recognizes invading pathogenic microorganisms, autologous or even allogeneic neoplastic cells, or allogeneic or heterologous transplants as “not self”, identifying them as not belonging to the organism. From that moment, it triggers an alarm and a joint innate and adaptive immune response to eliminate them or suppress a response deleterious to the human or animal organism (Goldsby R A, Kindt T J, Osborne B. Imunologia de kuby. 6 ed: ARTMED; 2008, 704 p; Janeway C, Travers P, Walport M, Slhlomchik M J. Immunobiology five. 5 ed: Garland Pub.; 2001. 732 p.; Voltarelli J C. Imunologia clinica na pratica medica: atheneu editora; 2009; Janeway C A, Jr., Medzhitov R. Innate immune recognition. Annual review of immunology. 2002; 20:197-216. Epub 2002/02/28; Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296 (5566):301-5. Epub 2002/04/16; Steinman R M, Banchereau J. Taking dendritic cells into medicine. Nature. 2007; 449 (7161): 419-26. Epub 2007/09/28.; Beutler B A. TLRs and innate immunity. Blood. 2009; 113 (7): 1399-407. Epub 2008/09/02; Moresco E M, LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93. Epub 2011/07/12) (1).
The recognition pattern of “not self”, of an invasive germ is performed by sentinel cells, represented by epithelial cells, mucosal cells, and the stromal cells, such as pericytes, dendritic cells, macrophages and fibroblasts, among others. These cells, strategically distributed throughout the body, have PRRs (Pattern Recognition Receptors) and DRRs (Danger Recognition Receptors) and SRR (stress response receptors) which are receptors respectively able to recognize a) standard identification molecules, characteristic of a wide range of microorganisms, b) certain patterns for chemical and physical of said inert substances and changes to metabolic stress, such as release of free radicals and tissue chemical changes, caused by ionizing radiation or by chemical substances, among others and c) stress receptor signals that identify viruses, starvation, ER stress and oxidative stress (Pulendran, B Annual Review Immunology 2015).
The PRR does not discriminate one specific individual microorganism, but the presence of microorganisms other than the human body. Each PRR receiver may bind to several different pathogens, recognizing as PAMPs (Pathogen Associated Molecular Patterns) carbohydrates, lipids, peptides and nucleic acids from bacteria, viruses, fungi or parasites that are not found in the human or animal body.
The DRRs discriminate that there is tissue damage, a dangerous situation caused by not live or inert agents. The DRRs identify DAMPs (Danger Associated Molecular Patterns) associated with tissue damage by toxic substances, radiation, or trauma, which cause metabolic stress, release of free radicals and chemical changes in tissue, recognized by these receptors.
The SRRs (stress response receptors) identify the signal of the metabolic stress caused by environment aggressions as viral infections or viral effective vaccines, amino acid starvation, ER(endoplasmic reticulum) stress, oxidative stress, through evolutionary conserved stress-sensing mechanism, that compose de Integrated Stress Response ISR as recently discovered (Janeway C, Travers P, alport M, Slhlomchik M J. Immunobiology five. 5th ed: Garland Pub.; 2001. 732 p.; Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296 (5566): 301-5. Epub 2002/04/16; Beutler B A. TLRs and innate immunity. Blood. 2009; 113 (7): 1399-407. Epub 2008/09/02; Moresco E M, LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13):R488-93. Epub 2011/07/12) (1).
Thus, sentinel cells via their PRRs and their DRRs, and SRRs have a role in the breakdown of which belongs (“self”) and which is does not belong (not “self”) and triggering inflammation and immune response, via recognition of PAMPs of invading pathogens and DAMPs caused by neoplastic cells, inert substances and toxic substances or modifications due to trauma, or stress response signals in infections in ISR leading to a situation of real danger to the human and animal organism.
Immediately, these activated sentinel cells give alarm signals, triggering the innate immune response through the NF-kB (Nuclear Factor-kB) signal translation system, leading to the secretion of pro-inflammatory cytokines and the IRF signal translation system, that produces Type I alpha and beta interferons. These cytokines, together, acting on cells and vessels, cause a local inflammatory process, initially to contain the invading agent, autologous (tumour cell), heterologous (microorganisms, prions, grafts and transplants) or allogeneic (grafts and transplants), or to repair danger situations. This contention happens through antibodies, pre-existing, opsonizing acute phase proteins and through leukocytes and macrophages, which engulf and start to destroy the extracellular and intracellular microorganisms respectively, or eliminating other etiologic agents of any kind.
Interaction and Integration of Innate Immunity with Adaptive Immunity
Simultaneously at the site of invasion, aggression and inflammation, the innate immunity sentinel cells with the APC role (Antigen Presenting Cells), such as dendritic cells and macrophages, phagocytosis and pinocytosis microorganisms or tumour cells, or transplanted cells, among other aggressors and process their antigens. These APC cells pulsed by the antigens migrate to regional lymph nodes and activate them. The APC cells in reactive lymph nodes, activated and mature present the antigens to lymphocytes, release cytokines and thereby induce, coordinate, polarize, amplify and maintain an adaptive immune response specific to the invading germs, or neoplastic cells, or to transplanted cells, or other offending agent, allowing them to be fought and eliminated, where feasible and the consequent cure of the infection or inflammation and repair and regeneration or wound healing (1) (3).
Thus, these immune mechanisms fight diseases through innate and adaptive primary or secondary responses in an integrated and synergistic way, performed by sentinels cells, APC function sentinels, and innate immunity effectors, cellular and molecular in conjunction with the cellular and molecular effectors of adaptive immunity that are respectively lymphocytes, cytokines and antibodies.
Thus, the interaction of the two immunities, innate and adaptive, in the context of an infection or immune response against an aggressor of any kind helps to fight the disease in an integrated and synergistic way. The integration of the two initially occurs by the action of the innate immunity cells with APC function, such as dendritic cells and macrophages, but mainly by the activity of dendritic cells, as they are the ones that are able to initiate an adaptive immune response against a primary infectious or parasitic agent, effectively protecting the body(2, 3). In secondary response memory, cells govern the silent immunological process that induce full protection (1, 2, 3, 14, 26, 38, 54, 56, 57, 58, 65)
Macrophages also function as APC cells, but are more specialized and involved as part of the effector loop in phagocytosis and in the elimination of microorganisms. B lymphocytes, when mature, are also APC cells and its most well-known action is the presentation of antigens to the T lymphocytes, within the framework of cooperation of both lymphocytes to produce antibodies against T-dependent antigen, and the secondary antibody response in lymph nodes and bonne marrow. Macrophages, like other myeloid cells, are also involved in suppressing immune response in mostly in chronic infections or in acute infections. In these case of chronic infections or tumours, its performance is unfavourable to the defense of the organism because it suppresses the immune response and create a chronic infection or tumour facilitation.
When co-stimulatory molecules are not expressed on the APC cell surface, by the absence of the alarm signal characterized by the lack of activation of PRRs, DAMPs and SRR by PAMPs, DAMPs and SRSs, only the first signal occurs, given by the TCR. After the TCR binds with the antigen, in the absence of the second signal, the T lymphocyte becomes tolerant to the specific antigen shown and aborts the immune response.
On the other hand, the CD 40L molecule of activated T lymphocytes, when it binds to the CD40 molecule on the APC cells, significantly increases the expression of CD80 and CD86 molecules, increasing the current response, which thus occurs only when the adaptive T response is already engaged in defending the body. The third signal given by cytokines such as IL-1, is given usually by the APC cells after the binding of co-stimulatory molecules and the emission of the second signal. The IL-1 released by the APC cells acts on lymphocyte cells and leads to the complete expression of the receptor for IL2 and to the production of IL2 and others polarization cytokines by virgin or memory lymphocytes engaged in response initiating clonal selection and expansion(primary) or memory clonal proliferation (secondary).
Therefore, the activation of innate immunity by pathogens or by aggression is the key to unleashing the second and third signals and the occurrence of a potentially effective immunity, through the full activation of T lymphocytes engaged in the response. Without the occurrence of the second and third signal, the response is aborted and generates a tolerance specific to the antigen presented.
At the same time that the neutrophils, monocytes and macrophages initiate combat to bacteria and to other infectious agents by the linkage of PAMPs with PRRs SRSs on antigen presenting cells (APC), they activate dendritic cells and macrophages, local and newly arrived or best activated by memory cells. These cells phagocytosis and pinocytosis bacteria and bacterial antigens, processing them and starting the maturation process. The activated and maturing dendritic cells now migrate to regional lymph nodes to present antigens and initiate immune response against the invading agent.
PAMPs alone can remodel lymph node feed arteriole and induce lymph node hypertrophy that is essential for an effective primary adaptive response occurs (4, 5). In secondary responses activated and pulsed by DCs cells in inflammatory territory, effector memory CD4-CD40-L+ cell migrate in a CD62P-dependent fashion into the reactive lymph nodes via HEVs and license dendritic cells for T cell priming against weak antigen, tolerate antigens and auto antigen starting an auto immune disease or improving an immune response in an ongoing infection or neoplastic disease(4). Also in inflammatory territories effector memory CD8 T cells secrete CCL3, that in turn activate MPCs to produce TNF alfa that induce PMNNs and Others MPCs to produce ROIs and clear intracellular bacteria. Unrelated intracellular pathogen sensitive to ROIs can also be clear by bystander activation in overlapping diseases or overlapping immune responses (6, 7).
The mature antigen-pulsed APC cells, especially dendritic cells, in lymph nodes, collaborate with the T and B lymphocytes and initiate the adaptive primary or secondary response (1). Dendritic cells are the most potent cells for the presentation of antigens and the only APC cells able to activate a virgin CD4 T lymphocyte and to start a new immune response (2,3).
After a period of approximately seven days in the lymph node, the collaboration between blank CD4 lymphocytes CD4-Th0), which become T CD4 Th2 or Tfh, with B lymphocytes and antigen presenting dendritic cells, initiates the differentiation of specific sensitized B lymphocytes. These B cells, now activated, recognize bacterial antigens by surface immunoglobulins, collaborate with T helper cells, cells after contact with these antigens, proliferate, mature, and differentiate into plasma cells that now release specific antibodies against this bacterium in a first moment outside of follicular node in the B cell area, in activated lymph nodes and after differentiation goes inside and induce germinal centre formation and secondary B cells responses with collaboration with CD4Tfh and others CD4T helpers cells. In secondary B cells responses, long lived plasma cells secrete Tcell dependent antibodies in bonne marrow, after initial production in lymph nodes (1,6) (8, 9). Infections of all types, bacterial, viral, fungal and parasitic may, in general, in the acute phase, evolve to a full cure with regeneration and healing, or for a cure with sequelae. They can also develop into an incurable chronicity, with or without control of the disease, to chronicity with healing, with or without sequelae, or to death.
Polarization of the Immune Response
The classic immune profiles known and induced by dendritic cells by direct and indirect contact with the different cytokines and generated by T CD4 cells are of four types(10-12):
a) cellular Th1 profile, which generates cellular immunity mediated by cells; (13) b) humoral Th2 profile, which generates humoral immunity mediated by antibodies(13);
c) tissue or inflammatory Th17 profile, which generates inflammatory tissue immunity, also mediated by cells and cytokines, which induce an important inflammation for the elimination of certain pathogens, and(13, 14)
d) Treg/Tr1 profile, which suppresses the immune response and controls, by inhibiting the other three profiles described above, ensuring the return of the body equilibrium state. (13, 15) e) New profiles have been stablished, as the Tfh (follicular Helper) of the humoral response (16), the Th9 profile for certain parasites like Helminths (17), Th22 that produce IL22 involved in Skin protection (17) or other profiles that may be discovered or no fully established(18).
Thus, the various profiles ensure the defense of the organism and the elimination of causative heterologous (infectious) agents invading and colonizing autologous (neoplasia). The last classic profile ensures the termination of the immune response, the balance, the regeneration, the safe return to normalcy and it prevents self-injury and allergy and is therefore vital to the health and preservation of the human species and animal, as much as the other profiles.
The phenomenon of polarization of the immune response is defined as the predominance of a certain immunological profile such as Th1 or Th2 at the expense of other profiles that become secondary or null. This phenomenon happens according to the type of attack suffered by the body. That is, according to the type of infection, pathology, and infection stage or pathology stage, the different type of immune response will be predominant, and it may be a cellular, humoral, tissue inflammatory, or immune-regulatory response, while other types of immune responses are inhibited, resulting in the phenomenon of polarization. (12)
By definition, there is a dominant profile in polarization, but other non-dominant profiles are also needed, and expressed in a complementary manner that will help eliminating the disease. For example, tuberculosis is the appearance of Th17 cells in the lung which allows Th1 cells to settle and may lead to cure this infection in the lung parenchyma (Stockinger, B. and Veldhoen, M. Differentiation and function of Th17 T cells. Current Opinion in Immunology, 19 (3), pp. 281-286. 2007). In viral infections, the CTL cells of Th1 profile destroy cells infected by viruses, to eliminate the virus. However, antibodies are required to prevent the virus from infecting other healthy cells and thus preventing the spread of infection. The coordinated assembly of the two profiles is essential for the healing of certain viral infections. Certain intestinal infections by extracellular Gram-negative bacilli require, for its cure, in the final stage, besides the Tfh and Th2 profile, the generation of a supplementary Th17 profile capable of generating a strong inflammation, necessary to eliminate this type of bacteria. (12)
In conclusion, due to the fact that the dendritic cells are the only professional APC cells capable to initiate a primary adaptive immune response and are the most potent in triggering a secondary specific immune response, in any profile, they are then commanding the interaction and integration of innate immunity with adaptive immunity to produce an effective immune response capable of curing a disease. Dendritic cells in collaboration with other APC and sentinel cells in contact with different aggressors in different functional states, in the inflammation sites, in the lymph nodes, in the spleen, in the mucous membranes, are able to lead, coordinate, polarize, and amplify the adaptive immune response governing them, primary and secondary, e.g., specific for the peptides of invading pathogens, which in this case is the most appropriate for the removal of the ongoing infection(1,2,3).
Therefore, dendritic cells and other APC cells are key cells of the innate immune response, since they evaluate the nature of the autologous and heterologous causative agent, i.e., the type of pathogen or colonizing cells and aided by the sentinel cells, they measure and evaluate the size of the heterologous or autologous aggression, its extension, its intensity and aggressiveness, besides commanding the adaptive response with the profile and the intensity required for the elimination of the pathogen. In other words, innate immunity contextualize the aggression in a primary response and recontextualize in a secondary effective one by the action of T B and some NK memory cells (19) (20) (8, 9, 20-31)
After differentiation, a re-differentiation can occur, induced by the microenvironment and/or the type of antigen or its presentation, in which a Th1 or Th2 profile can be exchanged for an inflammatory profile or an immunosuppressant profile or vice versa. This extreme plasticity of the immune system to differentiate or re-differentiate in either direction indicates a strategic window for manipulation of the immune system, during infection, when the direction taken by the polarization is not the best one for curing the infection process or neoplasia (32).
As an illustrative example, we have what happens in a severe infection or septicaemia, that induce sepsis with massive inflammation caused by cytokine, induced by the large number of microorganisms which touch the sentinel cells throughout the body, induces also a Th17 a profile, which in turn increases the inflammation more and therefore becomes detrimental, leading to tissue destruction, rather than inducing healing and paradoxically inducing late immunosuppression by the Treg/Tr1 profile and exhaustion state. In these cases the Th17 profile, by tissue destruction and the amplification of inflammation, is implicated in the generation of clinical complications such as severe ARDS (acute respiratory distress syndrome in adults), lung shock, renal failure, or shock, that compromises healing (4, 33, 34).
The re-differentiation of polarization for the Th1 or Th2 profiles, with the inhibition of massive inflammation, is the logical and strategic path for a designed or prepared immunotherapy to try to resolve this dramatic and deadly type of situation, during a severe infection or sepsis, which has a significant mortality and morbidity and for which antibiotics and other antimicrobials, in current patterns such as single mode, have disappointing anti-infective results. The same example applies to serious intra cellular bacterial, fungal, viral and parasitic infections, with extensive tissue destruction and massive inflammation, usually of poor prognosis.
The Use of Adjuvants to Stimulate Immune Response
The human and animal organisms do not usually produce antibodies against soluble proteins, necessitating the use of so-called nonspecific or unrelated adjuvants to obtain the desired immune response. These adjuvants used since the dawn of immunology, in immunizations and in vaccine applications, were and are made up of parts of microorganisms, mineral oils and other substances that activate the innate immunity, which then gives the alarm and control necessary for the development of desired immune response to the protein or to the vaccine in question (GOLDSBY RA, KINDT TJ, OSBORNE BA. IMUNOLOGIA D E KUBY. 6 ed: ARTMED; 2008. 704 p); (Janeway C, Travers P, alport M, Slhlomchik M J. Immunobiology five. 5 ed: Garland Pub.; 2001. 732 p.); (VOLTARELLI JC. IMUNOLOGIA CLINICA NA PRATICA MEDICA: ATHENEU EDITORA; 2009); (Janeway C A, Jr., Medzhitov R. Innate immune recognition. Annual review of immunology. 2002; 20:197-216. Epub 2002/02/28.); (Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296 (5566): 301-5. Epub 2002/04/16.): (Steinman R M, Banchereau J. Taking dendritic cells into medicine. Nature. 2007; 449 (7161): 19-26. Epub 2007/09/28.); (Beutler B A. TLRs and innate immunity. Blood. 2009; 113 (7): 1399-407. Epub 2008/09/02.); (Moresco E M, LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93. Epub 2011/07/12).
It should be noted that the use of adjuvants for immunization, despite being one of the oldest features, and still current, highly used and essential for vaccinations and for studies of immunology, was considered only as a useful nonspecific effect. It was not envisioned, for more than a century, its role in the innate immunity in the discrimination of what is “Self” and not “Self” and its unique and fundamental capacity to the survival of the human species and animals: to give the alarm signal and the command to start or not start, or inhibit, an integrated, protective or healing, innate and adaptive, immune response (GOLDSBY RA, KINDT TJ, OSBORNE BA. IMUNOLOGIA D E KUBY. 6 ed: ARTMED; 2008. 704 p); (Janeway C, Travers P, Walport M, Slhlomchik M J. Immunobiology five. 5 ed: Garland Pub.; 2001. 732 p.); (VOLTARELLI JC. IMUNOLOGIA CLINICA NA PRATICA MEDICA: ATHENEU EDITORA; 2009); (Janeway C A, Jr., Medzhitov R. Innate immune recognition. Annual review of immunology. 2002; 20:197-216. Epub 2002/02/28.); (Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296 (5566): 301-5. Epub 2002/04/16.): (Steinman R M, Banchereau J. Taking dendritic cells into medicine. Nature. 2007; 449 (7161): 419-26. Epub 2007/09/28.); (Beutler B A. TLRs and innate immunity. Blood. 2009; 113 (7): 1399-407. Epub 2008/09/02.); (Moresco E M, LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93. Epub 2011/07/12).
Treatment of Severe Infections, Sepsis, and Septic Shock
The current paradigm in infectious diseases is that antimicrobials are toxic selective drugs that destroy or block pathogens, like bacteria, fungus, virus and parasites, with little damage to the host and are responsible for the clearance of these agents. For this reason, they are traditionally employed in monotherapeutic approaches. (Reeves G, Todd I. Lecture notes on immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto V A, Nicodemo A C, Lopes H V. Antibióticos na pratica medic& 6th ed: Sarvier, 2007; Murray P R, Rosenthal K S, Pfaller M A. Microbiologia Medica. 5th ed: Mosby, 2006; Trabulsi L R, Alterthum F. Microbiologia. 5th ed: Atheneu Editora, 2008).
The treatment of severe infections, sepsis, and septic shock, combine more than one antibiotic, avoiding microbial resistance in combination with support measures to prevent or limit SIRS, ARSD or MODS or helped by preventive vaccines. Therefore, the current research is mostly focused on new antimicrobial drugs, drugs that prevent microbial resistance, and new medicines or biological agents to inhibit or control pro-inflammatory and immunosuppressive microenvironments, and vaccines.(34-41)
Paradoxically, the detailed analysis of the experimental model, that gave rise to the current paradigm in infectious diseases reveals an unexpected and not foreseen different conclusion: In that model, there are 3 players in the Petri dish: the pathogen, the antimicrobial drug and an inert culture medium that don't interfere in the interaction of the first 2 components. In that case, if the drug is effective we can say that the antibiotic made the elimination or clearance of the pathogen in vitro.
However, in the in vivo correlated situation, there are also 3 components: the antibiotic drug, the pathogen and the human or animal bodies, that are not an inert medium, and have an immune system with the same task of the antibiotic, that is, they also block and combat the pathogen. We cannot translate the conclusion of a system in vitro with 3 components and 2 variables to a system in vivo with 3 components and 3 variables. They are not scientifically comparable and the conclusion in vitro cannot be translated to the in vivo system to explain cure.
For that reason, in the case of the antibiotic that can eliminate the isolated bacteria in vitro, it is not possible to say that the same antibiotic is responsible for the clearance of this pathogen or responsible for the cure of the infection in vivo when its occurs. The only conclusion that can be made in that case is: the success of the antimicrobial treatment in the clearance of the pathogen and in the cure of infection in vivo depends on the joint action of the antimicrobial drug and the immune system.
In strong support of this view, the immune system is deficient in the extreme of ages, dysfunctional in elders and immature in the first years of age. In this periods of life, infections are usually more severe and frequent, and there are also a higher rate of morbidity and mortality, even when antibiotics are used in correct indication, dosing and timing.
Also in the case of severe secondary immune deficiencies, like terminal AIDS, terminal oncologic patients, other terminal immune compromised patients and in terminal severe primary immune deficiencies of any kind, cure with antimicrobial drugs are not possible. In the immune compromised host, the antibiotics are used in higher doses compared to the immune competent patient for the very same clinical or veterinary condition. In the undeveloped world, where most of human population lives, malnutrition compromises the fitness and functionality of the immune system.
The lack of sewerage and drinkable water supply submits these populations to constant aggressions by innumerable pathogens, compromising the efficiency of the defense system and provoking disease. This constant aggression and frequent illness create an unhealthy positive feedback loop, compromising continuously the immune system and health. Finally, the lack of protection from environment aggression also weakens the body and immune system. These three conditions combined in a synergic way also create an unhealthy positive feedback loop, that severely compromises the immunological system, and decreases the efficiency of antimicrobial drugs, shortening the lifespan of these populations. There is no available data supporting of the isolated action of antimicrobial medicines in vivo without the collaboration of the immune system, since humans and animals cannot live without a functional immune system and once invaded the immune system react by innate and adaptive responses that only finish after the clearance of the pathogen and the end of tissue repair and the return to homeostasis (7,8).
In agreement with this interpretation, there is no clear evidence in the literature of clearance of pathogen in vivo by the sole action of antibiotics or antimicrobial drugs. In conclusion, without a functional immune system, it is impossible to cure severe infections with antimicrobial drugs in the monotherapeutic approach. In contrast, the cure of some infections is possible without antimicrobial drugs. Altogether, these evidences pointed to a definitive and significant role exerted by the immune system in the cure reached by antimicrobial drugs in vivo in infections (Reeves G, Todd I. Lecture notes on immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto V A, Nicodemo A C, Lopes H V. Antibióticos na prática medic& 6th ed: Sarvier, 2007; Murray P R, Rosenthal K S, Pfaller M A. Microbiologia Medica. 5th ed: Mosby, 2006; Trabulsi L R, Alterthum F. Microbiologia. 5th ed: Atheneu Editora, 2008).
A new explanation should be formulated in order to better understand the cure induced by the antimicrobial drugs in vivo, independently of the, well known mechanism of action in vitro against microbes. The inventors propose a new concept, in which the antimicrobial drugs can be considered as equilibrium shifters (ES) in a host×pathogen competition, that favours the host immune system in a multivariable context. The variables are: concomitant diseases, traumas, age, sex, race, psychological health, innate and adaptive immunity, metabolism, nutrition, physiological flora microbiota, environmental aggression by drugs, and exposure to radiation, gases, pathogens and medical treatments.
What possibly occurs is that the antimicrobial drugs by their action against bacteria facilitate the work of the immune system in pathogen clearance, reverting the host×pathogen equilibrium competition and promoting the cure. The antimicrobial drugs would function as equilibrium shifters of the host×pathogen competition by significantly: weakening the pathogens action and reducing their numbers in vivo and by that way facilitating the role of the immune system in microbe clearance. Alternative outcomes are death or chronic infection, regardless of the use of antimicrobial drugs.
The application of this new concept in the context of the discovery of new treatments for severe or potential incurable infections/inflammatory syndromes, such as sepsis or septic shock deserves some considerations. As equilibrium shifters in the host versus pathogen balance, antimicrobial drugs have a compulsory partner in vivo, the immune system. By accepting the concept that antimicrobial drugs are not the main players in achieving cure but act as important and frequently necessary helper factors that contribute to shift the balance in favour of the host, in infection/inflammation disease, a primordial question emerges: how to change and improve an established initial exaggerated, ineffective, improper ore deleterious IR conducting the immune system to generate the best immunological response (IR) available, innate and adaptive capable to combat and make the clearance of the pathogen and at the same time having an physiological benefic anti-inflammatory action during the course of the treated disease.